The majority of children and adolescents with B-precursor acute lymphoblastic leukemia (ALL) have good responses to current therapy with 5-year survival rates of 84% in 1996-2003, as compared to 54% in 1975-77.1 To optimize the risk/benefit ratio, patients are stratified for treatment intensity based upon their risk of relapse.2 The majority of patients have prognostic factors that place them into the favorable or standard risk treatment groups. These patients generally have long relapse free survivals (RFS), although prediction of the individual patients who will fail therapy still remains a significant problem. Patients in the high risk treatment group are fewer in number and have not been as well studied. A detailed examination of this cohort of patients may provide insights into the genes and pathways that are fundamentally associated with outcome.
The white blood cell (WBC) count, age and presence of extramedullary disease at the time of diagnosis have been the primary criteria for assigning B-precursor ALL patients to risk groups.3 These groups have been further refined by the identification of sentinel genetic alterations (e.g., BCR/ABL or TEL/AML1 fusions) and the rate of response to initial treatment.4 The considerable diversity and varying responses to therapy has led to an effort to further refine risk stratification. Molecular techniques are being explored in order to classify patients on the basis of their leukemic cell gene expression signatures.5,6 Previous microarray studies have not only been effective in the identification of subtypes of leukemia, but in some cases they have also found these signatures to be associated with outcome.5,7 
The high-risk ALL Therapeutically Applicable Research to Generate Effective Treatments (TARGET) pilot project is a partnership between the National Cancer Institute and the Children's Oncology Group (COG) designed to use genomics to identify and validate therapeutic targets. We analyzed specimens from 207 of 272 (75%) of high-risk B-precursor ALL patients from the COG P9906 clinical trial in an effort to identify subgroups of these high-risk patients that were characterized by unique gene expression profiles or signatures. Our objectives in this study were three-fold: 1) to identify subtypes of high-risk B-ALL defined by characteristic gene signatures, 2) to determine if these subtypes are associated with specific clinical features and 3) to analyze the signature genes to gain insight into the biology of the subtypes. The results from these analyses may lead to improved diagnostics, modified definitions of risk-categories and development of new targeted therapies.